ALCON CANADA INC. v. ALCON RESEARCH, LTD., 2014 FC 791

Date: 20140825 Docket: T-1667-12 Citation: 2014 FC 791 BETWEEN: ALCON CANADA INC. AND ALCON RESEARCH, LTD. Applicants and APOTEX INC. AND THE MINISTER OF HEALTH Respondents PUBLIC REASONS FOR JUDGMENT ( Confidential Reasons for Judgment issued August 11, 2014 ) TABLE OF CONTENTS Page I. OVERVIEW ... 4 II. INTRODUCTION .. 4 III. THE PARTIES . 5 IV. THE ‘370 PATENT GENERALLY .. 6 V. THE EVIDENCE .. 8 A. For the applicant Alcon: 8

(1) Kingsley Koo . 8

(2) Dr Bhagwati Kabra . 8

(3) Dr Thorsteinn Loftsson . 8 B. For the respondent Apotex: 9

(1) Lisa Ebdon . 9

(2) Christopher Butler 9

(3) Lisa Lines . 10

(4) Dr John Kent 10

(5) Dr Michael Miller 10 VI. ISSUES . 11 A. Alcon’s overall position . 11 B. Apotex’s overall position . 12 VII. THE NOTICE OF ALLEGATION [NOA] 14 A. Alcon’s position on the NOA .. 16 B. Apotex’s position on the NOA .. 17 C. Jurisprudence and Principles Regarding a Notice of Allegation . 20 D. The scope of the NOA .. 23 VIII. BURDEN .. 27

IX. PERSON SKILLED IN THE ART . 29 X. THE ‘370 PATENT IN DETAIL .. 31 XI. CONSTRUCTION OF THE CLAIMS . 39 A. Jurisprudence and Principles Governing the Construction of a Patent and its Claims . 39 B. What do the Experts say? . 40 C. Construction of Claims 10 and 13 . 43 XII. THE INVENTION .. 45 A. Jurisprudence and Principles regarding the Inventive Concept 45 B. Alcon’s position on the Inventive Concept 46 C. Apotex’s position on the Inventive Concept 47 D. What do the experts say? . 48 E. The Inventive Concept 50 XIII. OBVIOUSNESS . 54 A. Jurisprudence and Principles on Obviousness . 55 B.

Alcon’s position on Obviousness . 57 C. Apotex’s position on Obviousness . 61 D. What do the experts say? . 68

(1) Doctor Loftsson . 68

(2) Doctor Miller 74

(3) Dr Kent 77 E. The Allegations of Obviousness Are Justified . 82 XIV. UTILITY .. 91 A. Jurisprudence / Principles Regarding the Promise of the Patent 92 B. Alcon’s position on the Promised Utility . 94 C. Apotex’s position on the Promised Utility . 96 D. What do the Expert’s Say? . 99

(1) Dr Loftsson . 99

(2) Dr Miller 100

(3) Dr Kent 102 E. The Promised Utility . 104 F. Jurisprudence/Principles Regarding Demonstrated and Sound Prediction of Utility . 107 G. Alcon’s Position on Demonstrated or Soundly Predicted Utility . 109 H. Apotex’s Position on Demonstrated or Soundly Predicted utility . 109 I. What do the Experts Say about Demonstrated or Sound Prediction of Utility? . 111 J. The promised utility was soundly predicted . 112 XV. CONCLUSIONS AND COSTS . 113 KANE J.

I.

OVERVIEW [ 1 ] This application, under the provisions of the Patented Medicines (Notice of Compliance) Regulations , SOR/93-133, as amended [ NOC Regulations ], seeks to prohibit the Minister of Health from issuing a Notice of Compliance [NOC] to Apotex in respect of its generic product (Apo-Travoprost Z, or the Apotex product) until the expiry of Canadian Letters Patent No 2,606,370 (the ‘370) on September 20, 2027. [ 2 ] Apotex submits that the NOC should be issued because the claims of the Patent at issue are invalid. [ 3 ] For the reasons that follow, I find that the allegations with respect to the invalidity of the claims at issue for obviousness are justified and the allegations with respect to invalidity for lack of utility are not justified. [ 4 ] The application is dismissed with costs to the respondent.

II. INTRODUCTION [ 5 ] The Patent at issue in this proceeding relates to Alcon’s product, an ophthalmic solution typically used for the treatment of glaucoma. [ 6 ] Glaucoma is a disease of the eye resulting in a progressive loss of vision due to increased intraocular pressure [“IOP”], which is the pressure within the aqueous humour of the eye. Reducing IOP is the only way known to treat glaucoma.

Such treatment is ongoing or “chronic” and requires the patient to take medication daily to maintain the IOP at a reduced level. [ 7 ] Alcon notes that prostaglandin analogues, such as latanoprost and travoprost, are effective in lowering IOP and have become “mainstays” of treatment.

Alcon further notes that travoprost is the active ingredient in Alcon’s TRAVATAN® and TRAVATAN Z® products, which are administered topically to the surface of the eye using a small, multi-dose bottle that contains travoprost in solution. [ 8 ] Such multi-dose topical ophthalmic solutions require preservatives to avoid microbial contamination. Contamination may result from repeated exposure to air, bodily fluids and tissues.

Single-dose products do not require preservatives because they are used only once. [ 9 ] The ‘370 Patent at issue claims formulations of travoprost, an anti-glaucoma drug, with a non-conventional preservative system to permit multi-use application. [ 10 ] Apotex now wishes to market its own product, Apo-Travoprost Z, which is also a multi-dose ophthalmic solution containing travoprost with a non-conventional preservative system. Apotex requires a NOC in order to do so. III. THE PARTIES [ 11 ] The applicant, Alcon, is a “first person” as described in the NOC Regulations .

It has listed the '370 Patent in accordance with the Regulations. Alcon obtained a Notice of Compliance [NOC] to sell its multi-dose ophthalmic formulation preserved against microbial contamination, Travatan Z. [ 12 ] The respondent, Apotex, is a “second person” as described in the NOC Regulations . In order to sell its generic product, Apo- Travoprost Z, it must obtain a NOC from the Minister of Health. [ 13 ] In accordance with the NOC Regulations , Apotex served Alcon with a Notice of Allegation [NOA] dated July 25, 2012.

In its NOA, Apotex alleges that Claims 10 and 13 of the ‘370 Patent are invalid on several grounds, as noted below, but now pursues only the allegations of obviousness and lack of utility. Apotex also alleges that it does not infringe any valid claim in making, constructing, using or selling its product. [ 14 ] The Minister of Health, who has various responsibilities under the NOC Regulations , including the issuance of a NOC to a “second person” such as Apotex, took no active role in these proceedings. IV.

THE ‘370 PATENT GENERALLY [ 15 ] Canadian Letters Patent No 2,606,370 were applied for by an application deemed to be filed with the Canadian Patent Office on September 20, 2007. The new Patent Act , RSC 1985 c P-4, governs this Patent, as it was applied for after October 1, 1989. [ 16 ] The application was filed under the provisions of the Patent Cooperation Treaty [PCT] and claims priority from a first application filed in the United States Patent Office on September 21, 2006.

This is the date upon which the issue of obviousness will be determined. [ 17 ] The date of filing in Canada, September 20, 2007 is the date upon which the issue of utility (demonstrated or soundly predicted) will be determined. [ 18 ] The publication date, i.e., the date at which the Patent was open to the public for inspection, was March 21, 2008. This is the relevant date for the purposes of the construction of the claims.

[ 19 ] The ‘370 Patent lists the inventors as Bhagwati P Kabra, Masood A Chowhan, L Wayne Schneider and Wesley Wehsin Han, all of the United States. Only Dr Kabra provided evidence in these proceedings. [ 20 ] The ‘370 Patent was issued to Alcon Laboratories Inc, US. [ 21 ] The term of the ‘370 Patent, unless declared as invalid, will expire 20 years from the date of the filing of the application in Canada, which is September 20, 2027. [ 22 ] There are 35 claims in the ‘370 Patent; however, only Claims 10 and 13 are at issue in this proceeding.

The construction of the claims and the inventive concept of the Patent are addressed below. V. THE EVIDENCE [ 23 ] The evidence was provided in the form of affidavits and transcripts of the cross-examination of the experts along with their exhibits. All experts were cross-examined. Each party also submitted the affidavits of law clerks to place documents on the record and attest to facts. [ 24 ] The evidence on the record includes the following: A. For the applicant Alcon:

(1) Kingsley Koo [ 25 ] Kingsley Koo is a law clerk at Alcon’s solicitor’s office. His affidavit attaches a variety of documents, such as the ‘370 Patent, Apotex’s Notice of Allegation, and Apotex’s prior art references.

(2) Dr Bhagwati Kabra [ 26 ] Dr Kabra is one of the inventors of the ‘370 Patent and describes Alcon’s work leading to TRAVATAN Z and the ‘370 Patent. Dr Bhagwati Kabra holds an MSc and PhD in Chemical Engineering. He has been employed by Alcon and its predecessors since 1993.

(3) Dr Thorsteinn Loftsson [ 27 ] Dr Loftsson is a Professor of Physical Pharmacy in the Faculty of Pharmaceutical Sciences at the University of Iceland. Dr Loftsson holds a MSc and PhD in Pharmaceutical Chemistry, as well as a MSc in Pharmacy. In addition to teaching and research, he is a Director of a small pharmaceutical company and Board Member of another. He is a member of several professional societies, the author of more than 270 publications, and he has delivered more than 100 invited lectures. He describes his expertise in the formulation of multi-use ophthalmic solutions.

He was asked by Alcon to, among other things, discuss the skills of the person skilled in the art, review the scientific background and common general knowledge related to self-preserved ophthalmic solutions, review the ‘370, identify the inventive concept of Claims 10 and 13, identify the utility of the Patent and respond to Apotex’s allegations relating to anticipation, obviousness and inutility. B. For the respondent Apotex :

(1) Lisa Ebdon [ 28 ] Lisa Ebdon is a law clerk at Apotex’s solicitor’s office. Her affidavit attaches a variety of documents, including Apotex’s Notice of Allegation, the prior art references, and a copy of the ‘370 Patent.

(2) Christopher Butler [ 29 ] Christopher Butler is the Office Manager at the Internet Archive, which operates the Wayback Machine, a database that provides access to archived versions of the Internet. Mr Butler attaches documents about SYSTANE products obtained using the Wayback Machine.

(3) Lisa Lines [ 30 ] Lisa Lines is a medical writer and PhD candidate in Health Services Research at the University of Massachusetts Medical School. Ms Lines attended and reported on the Association for Research in Vision and Ophthalmology [ARVO] 2006 annual meeting, including Alcon’s tear replacement product SYSTANE® FREE.

(4) Dr John Kent [ 31 ] Dr Kent earned a PhD in Pharmaceutics in 1969 and was employed by several pharmaceutical companies from 1965 until 2008. He has been a consultant to the pharmaceutical industry since 2008. Dr Kent worked at Allergan between 1990 and 2002. He describes his expertise in ophthalmic formulation development and notes that he developed more than 10 ophthalmic pharmaceuticals that were commercially launched. He was asked, among other things, to describe the person skilled in the art, to provide opinions on the

scope and meaning of the claims, the inventive concept of the claims, whether certain prior art documents were available to the public as of September 21, 2006, whether the prior art discloses the subject matter of the claims, the differences if any between the state of the art and the inventive concept of the claims (i.e. whether the Patent was obvious), the utility of the Patent and whether that utility had been demonstrated or soundly predicted. In addition, Dr Kent reviewed the affidavits of Dr Kabra and Dr Loftsson and provided comments.

(5) Dr Michael Miller [ 32 ] Dr Miller holds a PhD in Microbiology and Biochemistry. Dr Miller worked at Bausch & Lomb in various capacities between 1991 and 2002 and at Eli Lilly from 2003 to 2009 and is currently President of Microbiology Consultants, LLC. He describes his expertise in the field of ophthalmic compositions and antimicrobial preservation of such compositions including self- preserved ophthalmic compositions.

He was asked by Apotex, among other things, to provide a scientific primer, and to provide his opinion on the state of the art as of September 21, 2006, the inventive concept of the claims, the differences between the inventive concept and the state of the art and whether those differences would be self-evident. He was also asked to review and comment on the affidavits of Dr Kabra and Dr Loftsson. VI. ISSUES [ 33 ] The overall issue is whether to grant an Order prohibiting the Minister of Health from granting a Notice of Compliance to Apotex for its generic product (Apo-Travoprost

Z) until the expiry of the '370 Patent. This determination depends upon whether the allegations raised by Apotex as to the invalidity of particular claims of the '370 Patent are justified. [ 34 ] Apotex alleges that the claims at issue are invalid on the basis of obviousness and lack of demonstrated or soundly predicted utility. To provide the relevant context for the analysis of the allegations, the assessment of the evidence and my findings, a brief overview of the positions of Alcon and Apotex follows. A.

Alcon’s overall position [ 35 ] Alcon notes that the Patent relates to a self preserved multi-dose formulation, using multi-functional components to avoid microbial activity. The invention does not use benzalkonium chloride [BAK or BAC], which had been known to cause side effects. Alcon submits that there are at least four inventive concepts for the claims at issue and that the invention was not obvious.

Alcon further submits that although the inventive concepts are several and specific, the promised utility is simply to provide a formulation that passes USP preservative efficacy testing [PET] and is useful or provides another choice. Alcon submits that this utility was soundly predicted. [ 36 ] Alcon disputes that the promised utility is also to minimize or eliminate toxicological effects.

However, Alcon submits, that if this were the promised utility, it was also soundly predicted. [ 37 ] Alcon disputes Apotex’s new or revised assertion of promised utility; that the promised utility is to provide an “acceptable” pharmaceutical composition or formulation where “acceptable” means without the possibility of particulate matter forming. Alcon notes that this was not asserted as the basis for the allegation of lack of utility by Apotex in its NOA, and as such, this new basis for the allegation cannot be considered. B.

Apotex’s overall position [ 38 ] Apotex argues that Alcon seeks to read the inventive concept of the Patent in one way to support its inventiveness and to read it another way to support its utility, as simply being useful. [ 39 ] Apotex submits that the invention was obvious; Alcon sought to replace BAK with another preservative system to avoid the side effects and the prior art taught how to do so. In particular, Alcon need not have looked any farther than its own preservative system used in Systane Free or a system similar to that of Systane Free.

Apotex further argues that the prior art and common general knowledge would lead a POSITA to this invention. [ 40 ] Apotex now also submits, as a new or revised assertion, that the promised utility of the multi-dose formulation is to provide an “acceptable” formulation, meaning that particulate matter will not occur. Apotex’s original assertion of the promised utility is the use of the components of the invention in an aqueous ophthalmic solution so as to eliminate the need for BAK and to minimize or eliminate the toxicological effects.

Apotex submits that neither the original nor the revised promised utility was soundly predicted. [ 41 ] Apotex submits that Alcon cannot rely on the resolution of the particulate matter problem as part of the inventive concept yet deny that it is part of the promised utility. [ 42 ] Apotex also argues that it cannot be precluded from responding to this aspect of the inventive concept despite that it did not raise this as the promised utility in the NOA. [ 43 ] The overview of the parties’ positions understates the complexity of the arguments advanced in this application.

The position of both parties appears to have evolved and both have raised alternative arguments and have responded with alternatives to the alternatives, further complicating the determination of the key issues, the allegations of obviousness and lack of demonstrated and soundly predicted utility.

Although some of the issues raised by the parties are not determinative given my findings with respect to the scope of the NOA, construction of the claims, determination of the inventive concept, and determination of the promised utility, all of the arguments of the parties and the voluminous evidence have been carefully considered.

VII. THE NOTICE OF ALLEGATION [NOA] [ 44 ] In the Notice of Allegation, Apotex broadly alleges that all claims of the ‘370 are invalid on the basis of one or more of the following grounds; lack of novelty/anticipation, obviousness, lack of demonstrated utility, no sound prediction of utility and failure of utility. [ 45 ] With respect to the inventive concept, Apotex alleges at page 28: […] there is no invention in the claims of the ‘370 Patent, and therefore there is no inventive concept in any of the claims of the ‘370 Patent.

Alternatively, Apotex alleges that, if anything, the inventive concept of the claims of the ‘370 Patent is the use of the recited components ( e.g. zinc ions, borate/polyol complex, etc.) at their respective concentrations in the claimed aqueous ophthalmic solutions so as to eliminate the need for the preservative BAK, thus avoiding deleterious effects on the cornea. [ 46 ] With respect to the allegations of obviousness, Apotex set out the prior art relating to: zinc ions and preservatives in ophthalmic compositions including the prior art listed in the ‘370; borate/polyol complexes; travoprost; polyoxyl 40 hydrogenated castor oil; and, osmolality. [ 47 ] At page 33, with respect to borate/polyol complexes, Apotex notes: Further, an Alcon tear replacement product, SYSTANE® Free LIQUID GEL Lubricant Eye Drops, which was sold between 2005 and 2006 in the United States, incorporated a borate/polyol complex composed of boric acid, sorbitol and propylene glycol.

This product was also well known to the person skilled in the art. [ 48 ] At page 69-70, Apotex notes: Further, as of September 2006, the person skilled in the art would have understood the zinc ion/borate/polyol preservative system to be a viable alternative to BAK in ophthalmic compositions/solutions. The person skilled in the art would have been aware of Alcon’s own use of such a preservative system in their SYSTANE® artificial tears product.

Therefore, the person skilled in the art, as of September 2006, would have identified the use of a zinc ion/borate/polyol preservative system as a predictable solution addressing the use of BAK in an aqueous ophthalmic solution. [ 49 ] The NOA includes two publications by McCarthy: McCarthy 1985 ( Metal Ions and Microbial Inhibitors ) and McCarthy 1989 ( The Effect of Zinc Ions on Antimicrobial Activity of Selected Preservatives ) in the list of prior art with respect to zinc ions as preservatives at page 29. [ 50 ] With respect to the promised utility, Apotex alleges that the invention is the use of zinc ions in combination with borate and optionally polyols as a preservative system in multi-dose ophthalmic compositions.

Noting that the ‘370 indicates that BAK results in potential harmful effects on the cornea and that it should be avoided, Apotex concludes, “The preservative systems of the claimed ophthalmic compositions/solutions exhibit antimicrobial activity (“self preserved”) with concomitant minimization or elimination of toxicological effects (harmful effects on the cornea).

Hereafter, this will be referred to as the ‘Promised Utility’”. [ 51 ] Apotex alleges that it was well known that the treatment of glaucoma requires control of IOP and long term application of the drug to the eye and a POSITA would understand that because the intended use was to control IOP, compositions or solutions that are promised to minimize or eliminate toxicological effects would require evaluation, however, none had been done.

Apotex, therefore, alleges that Alcon has not demonstrated or soundly predicted utility. [ 52 ] The NOA notes that several claims are irrelevant, but sets out allegations of obviousness and lack of demonstrated or soundly predicted utility of all claims, as noted above. [ 53 ] The claims at issue in the present application are Claims 10 and 13. A.

Alcon’s position on the NOA [ 54 ] Alcon acknowledges that Apotex’s Notice of Allegation alleges invalidity of Claims 10 and 13 on the following grounds: the claimed invention is obvious in view of the prior art and certain Alcon products; and the ‘370 Patent promises “ophthalmic compositions/solutions [that] exhibit antimicrobial activity (“self-preserved”) with concomitant minimization or elimination of toxicological effects (harmful effects on the cornea)” and that the ‘370 Patent fails to demonstrate or soundly predict that promised utility. [ 55 ] Alcon disputes both allegations. [ 56 ] Alcon also notes that other issues raised in the NOA have not been pursued: for example, that other claims of the ‘370 Patent are anticipated and/or irrelevant and that the claims are broader than the invention.

Alcon notes that although these are not pursued, it does not accept that the claims are anticipated. [ 57 ] Alcon notes that the NOA serves two purposes; it allows the first person to know the case to meet and it limits the issues. Alcon submits that Apotex has exceeded the limits by raising new issues that were not in the NOA. [ 58 ] Alcon submits that the following issues were not raised in the NOA: that the prior art, specifically the McCarthy publications, set out limits on anionic species; the particulars of the Systane Free formulation; and, the allegation of lack of demonstrated or soundly

predicted utility for the revised or new promised utility of an acceptable formulation (based on Apotex’s premise that particulate matter is not acceptable for ophthalmic solutions). [ 59 ] Alcon argues that there is a distinction between responding to evidence that arises regarding the allegations set out in the NOA and advancing new allegations or further bases of invalidity for those allegations.

Alcon argues that responding to the evidence of an expert, in this case, Dr Loftsson, does not permit Apotex to raise new grounds of invalidity or new bases for the allegations set out in the NOA. [ 60 ] Alcon submits that Apotex cannot now argue that there is no sound prediction of acceptable ophthalmic solutions due to the particulate problem because this was not set out in its NOA nor is there such a promised utility. B. Apotex’s position on the NOA [ 61 ] Apotex submits that the NOA must provide adequate notice to permit the first person, Alcon, to decide whether to bring its Notice of Application.

In this case, Alcon had sufficient notice and did so. Alcon’s conduct in this litigation showed that they knew the case to meet. [ 62 ] Apotex notes that Alcon did not seek any further clarification from Apotex despite the invitation in the NOA to do so. In addition, Alcon did not submit an affidavit to indicate how it had been prejudiced by the alleged omissions.

Moreover, Apotex argues that it cannot be denied an opportunity to address the issues that Alcon raised in support of the validity of the claims at issue that could not have been anticipated and which were raised in response to the evidence of Alcon’s only expert witness, Dr Loftsson. [ 63 ] Apotex argues that Alcon ignored a key piece of the prior art relevant to the allegations of obviousness: that relating to its own product, Systane Free. Systane Free was a multi-dose ophthalmic composition that used zinc ions with a borate/polyol complex to avoid the need for a traditional preservative.

However, Alcon’s own expert did not consider Systane Free in his review of the prior art or in his opinion on obviousness and it appears that he was instructed to ignore Systane Free. [ 64 ] Apotex notes that its NOA clearly referred to Systane Free to support its allegations of obviousness and directed the reader to the details which could be found in another document referred to in a footnote.

Apotex subsequently led evidence to establish that Systane Free was marketed before 2006 for the purpose of correcting the misinformation of Alcon’s expert, Dr Loftsson, that the details of Systane Free were only available after 2006, the relevant date for the obviousness assessment. [ 65 ] With respect to the composition details of Systane Free, which Alcon argues are not relevant and should not be considered because they were not set out in the NOA, Apotex notes that the footnote in the NOA directs Alcon to one of its own documents. [ 66 ] The NOA also advised Alcon to make inquiries or seek clarification of the NOA and it did not.

Alcon requested other documents but did not request the document regarding Systane Free. [ 67 ] Apotex submits that Alcon cannot succeed in its argument that the NOA was deficient in not providing the formulation details of Systane Free given these circumstances and given that it was Alcon’s own product of which they had all the details. [ 68 ] With respect to the reliance on and reference to the prior art publications by McCarthy, Apotex notes that it referred to the publications in its NOA.

Apotex submits that it relies on the content of the McCarthy publications to counter Dr Loftsson’s evidence that nothing in the prior art indicated that the anionic species should be kept below 15mM.

Apotex notes that McCarthy did just that. [ 69 ] Apotex submits that Alcon’s position that there are at least four inventive concepts, including overcoming the formation of particulates, is based on the evidence of Dr Loftsson, which Alcon later adopted. [ 70 ] Apotex argues that a second person must be permitted to respond to issues raised by a first person that it could not have anticipated, otherwise there would be an incentive for the first person to raise new arguments to support the validity of a patent and take the second person off guard, knowing the second person would be prevented from responding.

Apotex submits that it has a right to respond to any issue or position raised by Alcon. [ 71 ] Apotex further submits that Alcon asserts that the NOA is deficient (i.e., that Apotex did not allege that the promised utility includes avoiding particulate matter) only to foreclose Apotex’s utility challenge. Apotex argues that the evidence revealed that there was no sound prediction that compositions falling within the asserted claims would not form particulate matter.

So, to avoid the claim being invalid for not meeting the promised utility of an acceptable formulation, Alcon seeks to prevent Apotex from raising the revised promise of utility. C. Jurisprudence and Principles Regarding a Notice of Allegation [ 72 ] Apotex relies on the jurisprudence which has held that a second person is not required to anticipate every theory of possible infringement, for example, AstraZeneca AB v Apotex Inc , 2005 FCA 183 , [2005] FCJ No 842 [ Omeprazole ] at para 11 .

Similarly in Novopharm v Pfizer , 2005 FCA 270 , [2005] FCJ No 1318 at para 16 , the Court of Appeal addressed the issue of the adequacy of the NOA, stating: [16] […] Whether Novopharm's NOA was adequate depends on whether it provided Pfizer with a sufficient understanding of the case it had to meet (supra at paragraph 4). The legal test of adequacy does not require Novopharm to anticipate all possible grounds of infringement, including Pfizer's speculative theory that the dihydrate could be used in the process of manufacturing Novopharm's bulk monohydrate. As noted by Evans J.A. in AstraZeneca AB v.

Apotex Inc. 2005 FCA 183 , [2005] F.C.J. No. 842 (QL) at paragraph 11 : A second person [the generic] should not be required to anticipate every theory of possible infringement, however speculative, in the

detailed statement supporting its allegations. [ 73 ] In Novopharm , the Court of Appeal noted that Pfizer was not left to guess at the real grounds for the allegation and also noted that Pfizer had raised the issue by filing evidence from its expert. [ 74 ] While the second person cannot be expected to anticipate every possible theory, the jurisprudence has established that the requirements of the NOA must be observed. [ 75 ] In Bayer Inc v Cobalt Pharmaceuticals Co , 2013 FC 1061 , [2013] FCJ No 1152 [ Bayer ] at paras 34-36 , Justice Hughes emphasized the requirement for the second person to raise all the facts and legal arguments it will rely upon in its NOA and that it cannot raise new arguments, new allegations, new facts or new prior art documents that are not set out in the NOA.

Justice Hughes acknowledged that this approach may seem “draconian” but that “it is equally draconian for the first person who decides to institute proceedings to face shifting allegations and facts” and added, “As matters stand now, the Court must reject arguments based on facts or documents not set out in the Notice of Allegation nor can the Court address new allegations” . [ 76 ] This principle has been applied to issues that arose after the NOA had been served and which the second person would not have been aware. [ 77 ] In Pfizer Canada Inc v Mylan Pharmaceuticals ULC , 2011 FC 547 , [2011] FCJ No 686 at paras 197-198 , Justice Hughes addressed Mylan’s argument that some of the testing data in the Patent at issue was inaccurate.

The NOA did not raise the issue whether the testing and data set out in the patent accurately presented what was done at Eisai.

Justice Hughes held that the Court could not consider such matters noting that “The issue in these NOC proceedings must be determined on the basis of what is set out in the Notice of Allegation.” [ 78 ] The Court of Appeal agreed, noting that Justice Hughes was aware that Mylan could not have known that the data was inaccurate until after the NOA was served and could not, therefore, have included such an allegation in its NOA ( Pfizer Canada Inc v Mylan Pharmaceuticals ULC , 2012 FCA 103 , [2012] FCJ No 386).

However, the NOA did not include the allegation that the work done by the applicant Eisai was not fully and accurately set out in the Patent. The Court stated at para 29: 29 It is well established that a Notice of Allegation frames the proceeding under the NOC Regulations , and that any allegation which is not included in that notice cannot be addressed in the proceeding: […] The special proceedings under the NOC Regulations are meant to be

summary. There is no discovery phase, and the proceedings are thus necessarily limited to the legal grounds and specific factual allegations set out in a Notice of Allegation, which cannot be subsequently amended.

This is a well understood feature of a proceeding under the NOC Regulations . [ 79 ] The Court of Appeal also noted at para 31 that the scope of allegations in an NOA must be determined in each case with a view to the language of the NOA and the evidence and that each case is highly fact-specific. [ 80 ] The lack of an affidavit has also been found to be a relevant factor in the determination whether the first person has been prejudiced by new issues that were not raised in the NOA. [ 81 ] In Aventis Pharma Inc v Apotex Inc , 2006 FCA 64 , [2006] FCJ No 208 at para 15 , the Court of Appeal found that the applications judge had considered the sufficiency of the NOA as it related to the issue of sound prediction, applied the relevant law and determined that the NOA had put Aventis on notice of the sound prediction argument.

The Court of Appeal confirmed that the applications judge properly considered the lack of an affidavit on the part of Aventis “to be telling” in her consideration of the sufficiency of the NOA. [ 82 ] The Court of Appeal made similar comments in Omeprazole , above, at para 13 regarding the lack of an affidavit on the part of AstraZeneca to describe how it had not been able to decide whether to challenge Apotex's NOA because of the lack of specificity in the NOA. D.

The scope of the NOA [ 83 ] The scope of the allegations must be determined in each case based on the language of the Notice of Allegation at issue as well as the evidence submitted. [ 84 ] In the present case, the Notice of Allegation raised allegations of invalidity based on obviousness and lack of demonstrated and soundly predicted utility based on the promised utility as Apotex originally alleged, i.e., the use of zinc ions in combination with borate and, optionally, polyols as a preservative system in multi-dose ophthalmic compositions with concomitant minimization or elimination of toxicological effects (harmful effects on the cornea).

The NOA did not allege lack of soundly predicted utility of an acceptable ophthalmic composition, which Apotex now asserts. [ 85 ] The case law is clear that the generic or second person cannot craft new arguments, or raise new allegations, new facts or new prior art documents which were not set out in the Notice of Allegation. [ 86 ] Apotex does not rely on new prior art as it was all set out in the NOA, including the references to Systane Free and McCarthy. [ 87 ] Systane Free was set out specifically in the NOA and this was sufficient notice to Alcon that it would be relied on as part of the prior art.

Alcon was directed to the details of the product, and given that it was an Alcon product, Alcon cannot credibly argue that the footnote reference was not sufficient. [ 88 ] With respect to the reference to McCarthy, both publications were referred to in the NOA, albeit not with details about why the publications would be relied on.

[ 89 ] Nor does Apotex rely on new allegations; the allegations remain obviousness and lack of demonstrated or soundly predicted utility.

However, Apotex raises new and different underlying facts to support the allegations of invalidity by asserting the promised utility of an acceptable formulation, meaning one without particulate matter. [ 90 ] I am not persuaded by Apotex’s argument that, because Alcon did not identify the resolution of the particulate problem as one of the inventive concepts in its Notice of Application, Apotex was not aware that the inventive concept was a live issue and it must now be permitted to assert a new basis for its allegation of lack of demonstrated or soundly predicted utility that is more closely aligned with this proposed aspect of the inventive concept.

It is not unusual or surprising that Alcon would assert its view of the inventive concept or would dispute the inventive concept asserted by Apotex. [ 91 ] The issue of the revised promise of utility of an acceptable formulation is a new basis for the allegation of lack of demonstrated or soundly predicted utility. Apotex now seems to put more reliance on this promise than its original assertion of the promised utility. However, Apotex also argues that resolving the particulate problem is not part of the inventive concept.

Apotex alternatively argues that, if the Court finds that it is, the promised utility must align with this aspect of the inventive concept. [ 92 ] The jurisprudence is clear; the proceedings are limited to the legal grounds and specific factual allegations set out in a Notice of Allegation. [ 93 ] I have considered whether allowing Apotex to raise this new basis for the allegation of lack of soundly predicted utility, although not specifically forecasted and not set out in its NOA, causes Alcon to “face shifting allegations and facts” . [ 94 ] Apotex has clearly raised a new factual basis or argument that was not in the NOA to buttress or refine its allegations of lack of utility.

On the other hand, Alcon did not submit an affidavit to provide evidence of how it was prejudiced in responding to the new argument.

Alcon brought this application and raised many arguments in response to Apotex as well as new issues that could not have been anticipated prior to Dr Loftsson’s evidence. [ 95 ] With respect to the new assertion regarding promised utility, I must agree with Justice Hughes in Bayer above, “As matters stand now, the Court must reject arguments based on facts or documents not set out in the Notice of Allegation nor can the Court address new allegations.” The Court will not address the allegation of lack of utility based on the promise of an “acceptable” formulation. [ 96 ] However, much of Apotex’s detailed arguments regarding the particulate issue is in response to Alcon’s argument that this is part of the inventive concept.

Therefore, Apotex may respond to Alcon’s position on the inventive concept but it cannot assert a revised promise of an “acceptable’ (i.e. no particulate matter) formulation as the basis for its allegations of invalidity based on lack of utility. [ 97 ] Despite my conclusion that the revised assertion of the promise of utility is beyond the scope of the NOA, it has no bearing on the outcome because the inventive concept does not include finding the solution to the particulate problem. VIII.

BURDEN [ 98 ] Apotex argues that it has put the issues of lack of utility (demonstrated and soundly predicted) and obviousness into play and Alcon now bears the burden of establishing the allegations are not justified.

Apotex argues that Alcon has not met this burden on a balance of probabilities and that in the event the Court finds the evidence is evenly balanced, it must find that Alcon has not met its burden. [ 99 ] The jurisprudence has settled who bears the burden of proof of the allegations. [ 100 ] As I noted in T-1666-12 ( Alcon v Apotex ), which was heard immediately before this application and which deals with a different patent, as a starting point, where the validity of a patent is at issue, the patent will be presumed to be valid.

However, where a generic manufacturer (a second person), in this case Apotex, raises allegations of invalidity and adduces some evidence capable of establishing the invalidity of the patent, the generic is said to put the issue “into play”.

The burden then moves to the brand or applicant (first person), in this case, Alcon, to establish on a balance of probabilities that all of the allegations of invalidity are not justified: see Lundbeck Canada Inc v Ratiopharm Inc , 2009 FC 1102 , [2009] FCJ 1466; Abbott Laboratories v Canada (Minister of Health) , 2007 FCA 153 , [2007] FCJ No 543 at paras 9-10 ; Pfizer v Canada (Minister of Health) , 2007 FCA 209 , [2007] FCJ No 767 at para 109 (FCA); Allergan Inc v Canada (Minister of Health) , 2012 FC 767 [ Allergan ] at para 42 affirmed in the result 2012 FCA 308 ; Pfizer Canada Inc v Pharmascience Inc , 2013 FC 120 , [2013] FCJ 111 at paras 24-27 ; Bayer v Cobalt , 2013 FC 573 . [ 101 ] Justice O’Reilly set out the approach to be followed with respect to the burden of proof in Pfizer Canada Inc v Apotex Inc , 2007 FC 26 , [2007] FCJ No 36 (aff’d 2007 FCA 195 , leave to appeal refused 32169 (November 1, 2007)) at paragraphs 9 and 12, characterizing the burden on the respondent as “an ‘evidential burden’-- a burden merely to adduce evidence of invalidity” .

The respondent must adduce evidence to give its allegations an air of reality, and if it does so, it has put the issues “into play” and the presumption of validity no longer applies. The applicant must then discharge its legal burden of proof to the satisfaction of the court on a balance of probabilities. [ 102 ] In the present case, if the generic, Apotex, does not adduce any evidence with respect to a ground of invalidity alleged, then the presumption is not rebutted.

Similarly, if Apotex adduces some evidence but that evidence is insufficient to meet its evidential burden or does not have an “air of reality” , the issues would not be put into play and Alcon would continue to rely on the presumption of validity to obtain its prohibition order. [ 103 ] However, if Apotex presents sufficient evidence to give its allegations an air of reality, then the presumption of validity is rebutted and the issue then becomes whether Alcon has established that Apotex's allegations of invalidity are not justified. [ 104 ] In Allergan at para 42 , Justice Hughes set out the same principles noted above which he had set out in his earlier decision in

GlaxoSmithKline Inc v Pharmascience Inc , 2011 FC 239 , [2011] FCJ No 287 at paras 43 and 44 , where he noted six steps in the assessment of the allegations and the applicable burden of proof. Justice Hughes indicated, following step 5, which is the weighing of the evidence on a balance of probabilities: 6.

If the evidence weighed in step 5 is evenly balanced (a rare event), the Applicant (first person) will have failed to prove that the allegation of invalidity is not justified and will not be entitled to the Order of prohibition that it seeks. [ 105 ] In Biovail Corp v Canada (Minister of Health) , 2010 FC 46 , [2010] FCJ No 46 at paras 40-41 and 107 , Justice Kelen applied the six step approach, set out his analysis of the law to the evidence, and found that the evidence was evenly balanced at the obvious to try step, noting, at para 107: […] Because the applicant has the onus of proof and because the Court has concluded that the evidence on this important “obvious to try” test criteria is evenly balanced, the applicant has not satisfied its onus to prove, on a balance of probabilities, that the allegation in this regard was unjustified.

For this reason, the Court must dismiss this application. [ 106 ] In the present case, Apotex raised allegations in its NOA and led sufficient evidence as to the invalidity of the Patent on the basis of obviousness and lack of demonstrated or soundly predicted utility to put those broad allegations and issues into play. As noted above, the allegation of lack of utility based on the revised assertion of promised utility is beyond the scope of the NOA. Alcon now bears the burden of establishing on a balance of probabilities that the allegations are not justified. IX.

PERSON SKILLED IN THE ART [ 107 ] There is no dispute about the qualifications of the person of skill in the art [POSITA], also referred to as the skilled person. [ 108 ] Dr.

Loftsson proposes, at para 21 of his affidavit, that the skilled person “is a pharmaceutical formulator or a person with an undergraduate degree in, for example, organic chemistry, biochemistry, medicinal chemistry or chemical engineering” and “would likely also hold a graduate degree in pharmaceutical sciences or pharmaceutics, with 3 to 5 years of experience in the formulation of ophthalmic products, including solutions”. [ 109 ] Dr Millar states, at para 46 of his affidavit, that the skilled person would have a PhD in microbiology or chemistry (or a related field) with at least a few years of experience in the development of ophthalmic formulations or would have a BSc or MSc in microbiology or chemistry (or a related field) with significant experience (five years or more) in the development of ophthalmic formulations.

He added that the skilled person would work as part of a multi- disciplinary team and draw on his own skills and the specialized skills of others to solve a formulation problem. [ 110 ] At para 45 of his affidavit, Dr Kent expresses the view that the skilled person would be a team of persons that includes pharmaceutical scientists/formulators and microbiologists who would have knowledge of how to formulate ophthalmic compositions, in particular self- preserved multi-dose ophthalmic solutions.

Representative individuals on the team would have a PhD in chemistry, pharmacy, microbiology or a related field with limited experience or a BSc or MSc with more practical experience (five or more years) in the formulation of such preserved ophthalmic formulations. [ 111 ] The POSITA for the ‘370 can, therefore, be described as: The team of person that includes pharmaceutical scientists / formulators and microbiologists. These persons have knowledge of how to formulate ophthalmic compositions, in particular, preserved multi dose ophthalmic solutions for topical application.

Representative individuals on the team would have a Ph.D. in chemistry, pharmacy, microbiology or a related field with limited experience (up to 3 years) or a B.Sc. or M.Sc. with more practical experience (5 or more years) in the formulation of such preserved ophthalmic formulations. X. THE ‘370 PATENT IN DETAIL [ 112 ] The title of Canadian Patent 2,606,370 is self-preserved aqueous pharmaceutical compositions . [ 113 ] At page 1, the Background of the Invention provides: The present invention is directed to self-preserved pharmaceutical compositions.

More specifically, the invention is directed to the provision of aqueous, multi-dose pharmaceutical compositions that have been formulated so as to have sufficient antimicrobial activity to satisfy the preservation efficacy requirements of the United States Pharmacopeia (“USP”) and analogous guidelines in other countries, without requiring a conventional antimicrobial preservative, such as benzalkonium chloride, polyquaternium-1, hydrogen peroxide (e.g., sodium perborate), or chorine-containing agents.

The ability to achieve self-preservation is based on a unique combination of formulation components and criteria. [ 114 ] The Patent then explains that many pharmaceutical compositions are required to be sterile and that procedures to do so are well known to POSITAs. It notes that the sterility of multi-dose products may be compromised due to their exposure to the atmosphere and other sources of contaminants.

Some means of preventing contamination is necessary; either a chemical agent or a packaging system. [ 115 ] The Patent then notes that in order to minimize the potential for harmful effects on the cornea, it is preferable to use anti- microbial preservatives that are relatively non-toxic at the lowest possible concentrations (described as “the minimum amounts required in order to perform their anti-microbial functions” ). [ 116 ] The Patent notes that the balance between the antimicrobial efficacy and the toxicological effects of these preservatives is

sometimes difficult and that the lower concentrations may be insufficient to achieve the required level of antimicrobial preservation. [ 117 ] At page 3, the Patent states the need to address this challenge as follows: Thus, there is a need for a means of enhancing the activity of anti-microbial agents so that very low concentrations of the agents can be utilized without increasing the potential for toxicological effects or subjecting patients to unacceptable risks of microbial contamination and resulting ophthalmic infections. [ 118 ] The Patent notes the approach of using multi-functional components to enhance the antimicrobial activity of ophthalmic compositions and identifies references in the art on the use of multifunctional components, including several US patents. [ 119 ] The Patent states at page 3: The use of zinc to enhance the antimicrobial activity of pharmaceutical compositions, including ophthalmic solutions, is well known.

See, for example, the following articles and patent publications, as well as U.S.

Patent No. 6,348,190 and JP 2003-104870, cited above (which refers to the art relating to multifunctional components.) [ 120 ] The Patent then sets out the references in the art regarding zinc, including: McCarthy, “Metal Ions and Microbial Inhibitors”, Cosmetic & Toiletries , 100:69-72 (Feb. 1985); Zeelie, et al., “The Effects of Selected Metal Salts on the Microbial Activities of Agents used in the Pharmaceutical and Related Industries”, Metal Compounds in Environment and Life , 4:193-200 (1992); [ 121 ] The Patent also notes Zeelie, 1998 and McCarthy, 1980 and several US Patents. [ 122 ] At page 4, the Patent indicates: The present invention is directed to the provision of improved preservative systems containing zinc ions.

The compositions of the present invention are multi-dose products that do not require a conventional antimicrobial preservative (e.g., benzalkonium chloride), and yet are preserved from microbial contamination. Such compositions have been referred to in the art as being “preservative free” (see, e.g., U.S. Patent No 5,597,559 issued to Olejnik, et al.). Compositions that are preserved from microbial contamination as a result of the inherent antimicrobial activity of one or more components of the compositions are also referred to in the art as being “self-preserved” (see, e.g., U.S.

Patent No 6,492,361 issued to Muller, et al.). [ 123 ] The Patent directs the reader to the 1997 publication of Kabara et al regarding preservative free and self preserving pharmaceutical compositions. [ 124 ] At pages 5-6, the

Summary of the Invention states: The present invention is directed to the self-preservation of aqueous ophthalmic compositions via the use of very low concentration of zinc ions. The present invention is based in part on the finding that in order to utilize low concentrations of zinc ions to self-preserve multi-dose ophthalmic compositions having ophthalmically acceptable pH and osmolality values, certain formulation parameters must be maintained.

Specifically, the concentration of buffering anions utilized to maintain the pH within an ophthalmically acceptable range must be limited to an amount of 15 millimolar (“mM”) or less in order to avoid interfering with the anti-microbial activity of the zinc ions.

In addition, it has been determined that the antimicrobial activity of the zinc-containing compositions of the present invention can be further enhanced by the use of zinc ions in combination with borate or a borate/polyol complex, and that if such a combination is utilized, the use of propylene glycol is strongly preferred, so as to avoid ionic interactions between anionic species by other polyols (e.g., sorbitol) and the zinc cations. It has also been determined that the performance of the zinc-based preservative systems of the present invention is further enhanced by: (

i) limiting the amount of multivalent metal cations other than zinc (e.g., calcium and magnesium) in the compositions of the present invention; and (ii) limiting the amount of ionized salts (e.g., sodium chloride and potassium chloride) in said compositions. As described in greater detail below, the compositions of the present invention are preferably free of or substantially free of both ionized salts and multivalent metal cations other than zinc. The self-preserved, multi-dose compositions of the present invention have several advantages over existing ophthalmic formulations that are either: (

i) packaged as a “single dose” or “unit of use” product, so as to avoid the inclusion of any antimicrobial preservative (e.g., BION®TEARS Lubricant Eye Drops, which is marketed by Alcon Laboratories, Inc.), or (ii) preserved by means of a so-called “disappearing” preservatives, such as the chlorite-based system described in U.S. Patent Nos. 5,424,078; 5,736,165; 6,024,954; and 5,858,346 (e.g., the artificial tears product “REFRESH™ Tears”, which is marketed by Allergan), or the peroxide-containing system described in U.S.

Patent Nos. 5,607,698; 5,683,993; 5,725,887; and 5,858,996 (e.g., the artificial tear product “GenTeal™ Tears”, which is marketed by CIBA Vision). Unlike these existing products, the multi-dose ophthalmic compositions of the present invention are able to satisfy the USP preservative efficacy requirements, as well as analogous requirements in other countries, including the Japanese Pharmacopoeia (“JP”) and European Pharmacopoeia (“EP”) preservative efficacy standards, without employing any conventional antimicrobial preservatives, such as chlorite or hydrogen peroxide.

The above-discussed findings regarding the zinc may be applied to enhance the antimicrobial activity of various types of pharmaceutical compositions. However, the present invention is particularly directed to the provision of aqueous ophthalmic solutions that are effective

in preventing microbial contamination in the absence of conventional antimicrobial preservatives, such as benzalkonium chloride (“BAC”), polyquaternium-1, chlorite or hydrogen peroxide. [ 125 ] At pages 6a-6c various embodiments of the invention are described. The invention is indicated to provide “a use of travoprost in a composition or solution of the invention for control of intraocular pressure” .

A detailed description of the invention commences at page 6c and describes the preferred concentration of zinc ions, the preferred concentration of anionic species, the preference to not include multivalent buffering anions other than borate-polyol complexes, and other such preferred and non-preferred substances. [ 126 ] At page 10, the Patent states: The present invention is particularly directed to the provision of multi-dose, self-preserved ophthalmic compositions that have sufficient antimicrobial activity to allow the compositions to satisfy the USP preservative efficacy requirements , as well as other preservative efficacy standards for aqueous pharmaceutical compositions, without a conventional antimicrobial preservative. [ 127 ] At page 11, the preservative efficacy standards for multi-dose ophthalmic solutions in the US and other countries are set out in a chart. [ 128 ] At pages 11-15 various optional substances, concentrations and therapeutic agents are described. [ 129 ] At page 13, the Patent indicates that the invention is “particularly directed” to the use of the self preserved multi-dose ophthalmic compositions in connection with the treatment of certain conditions, and that the compositions are particularly useful in the field of artificial tears, ocular lubricants and other compositions used to treat dry eye as well as other conditions involving ocular inflammation or discomfort.

Due to direct application to the eye, the Patent notes that the composition should be formulated to have a pH and tonicity compatible with the eye. [ 130 ] The preferred pH range for compositions intended for direct application to the eye is noted to be “in the range of 4 to 9, preferably 5.5 to 8.5, and most preferably 5.5 to 8.0” . Noting that a slightly alkaline pH increases the antimicrobial activity, the Patent states “The use of a pH in the range of 7.0 to 8.0 is therefore preferred” . [ 131 ] At page 14, the Patent notes that where cationic or anionic excipients are utilized adjustments may be required.

It states, “For example, the nonionic surfactant polyoxyl 40 hydrogenated castor oil can be used for solubilization or stabilization of drugs, such as travoprost.

However, it has been determined that 12-hydroxy stearic acid, an anionic compound that has been determined to be present as an impurity and potential degradation product of the excipient polyoxyl 40 hydrogenated castor oil, interacts with zinc and forms particles.” [ 132 ] The Patent then indicates at lines 28-31 that to avoid the particle formation in a composition containing these components the pH of the composition needs to be in the range of 5.0-6.0 and preferably 5.5-5.9, and directs the reader to Example Y. [ 133 ] At pages 15-38 Examples A-Z and AA-DD describe the embodiments or aspects of the invention. [ 134 ] The 35 Claims of the Patent are set out at pages 40-41. [ 135 ] Only two claims, 10 and 13, are at issue in this application.

As Claim 10 is dependent on Claims 1-9, which in turn are dependent in a cascading manner from Claim 1, it is also set out. [ 136 ] Claim 1 - A multi-dose, self-preserved ophthalmic composition, comprising zinc ions at a concentration of 0.04 to 0.4 mM, wherein the concentration of anionic species present in the composition is less than 15 mM. [ 137 ] Claim 10 - A composition according to any one of Claims 1-9, further containing travoprost as a therapeutically active agent. [ 138 ] Claim 13 - A topical ophthalmic solution comprising: • 0.004 w/v % travoprost; • polyoxyl 40 hydrogenated castor oil; • a preservative system comprising (

a) boric acid, (

b) propylene glycol, (

c) sorbitol, and (

d) zinc chloride in a concentration of 0.04 to 0.4 mM; • an amount of sodium hydroxide and / or hydrochloric acid to adjust the pH range of the solution to 5.5 to 5.9; and • purified water; wherein o the solution is free of benzalkonium chloride or another antimicrobial preservative; o the concentration of the anionic species present in the composition is less than 15 mM; and o the osmolality is 250 to 330 mOsm/kg. [ 139 ] As noted, Claim 10 depends on cascading and other dependencies among Claims 1 to 9. Alcon submits that Claim 10 read according to Claims 9, 5, 3 and 1 claims a multi-dose, self-preserved ophthalmic composition comprising: • travoprost;

• zinc ions between 0.1 to 0.4 mM; • a borate/polyol complex in which the polyol is propylene glycol and sorbitol; • wherein the concentration of o anionic species < 15 mM o multivalent buffering anions < 5mM; o multivalent metal ions < 5 mM; and o ionized salts < 50 mM. [ 140 ] This reading of Claim 10 is supported by the experts. XI. CONSTRUCTION OF THE CLAIMS A. Jurisprudence and Principles Governing the Construction of a Patent and its Claims [ 141 ] The principles governing claim construction are well settled. [ 142 ] Justice Hughes provided a useful

summary of the relevant principles following a review of all the jurisprudence in Pfizer Canada Inc v Pharmascience Inc , 2013 FC 120 , [2013] FCJ No 111: [64] There have been many judicial instructions as to the construction of a claim.

To summarize: • construction must be done before considering the issues of validity and infringement; • construction is done by the Court alone, as a matter of law; • the Court is to construe the claim through the eyes of the person skilled in the art to which the patent pertains; • the Court may obtain the assistance of experts to explain the meaning of particular words and phrases, and as to the state of the art as of the date the claim was published; • the Court should read the claim in the context of the patent as a whole, including the description and other claims; • The Court should avoid importing this or that gloss from the description; • the Court should not restrict the claim to specific examples in the patent; • the Court should endeavour to interpret the claim in a way that gives effect to the intention of the inventor; • the Court should endeavour to support a meritorious invention.

B. What do the Experts say? [ 143 ] Dr Loftsson provides his opinion on the construction of the claims beginning at para 199 of his affidavit.

He defines “multi- dose, “self- preserved” and “anionic species” in the same way as the other experts. [ 144 ] Dr Loftsson notes that Claims 1-9 relate to multi-dose, self preserved ophthalmic compositions, where no active ingredient is specified. [ 145 ] At para 211 Dr Loftsson states that Claim 10 claims a composition of any one of claims 1-9 further containing travoprost as a therapeutically active ingredient. [ 146 ] With respect to Claim 13, Dr Loftsson indicates at para 215 that it covers a topical ophthalmic solution with the following elements: 0.004 w/v % travoprost; polyoxyl 40 hydrogenated castor oil (i.e.

HCO-40); a preservative system comprising o boric acid, o propylene glycol o sorbitol; o zinc chloride in a concentration of 0.04 to 0.4 mM;

sodium hydroxide and/or hydrochloric acid to adjust the pH range of the solution to 5.5 to 5.9; and purified water; Claim 13 further requires that: o the solution is free of benzalkonium chloride (BAK) or another antimicrobial preservative; o the concentration of the anionic species present in the composition is less than 15 mM; and o the osmolality is 250 to 330 mOsm/kg. [ 147 ] At para 216 he adds: As claim 13 relates to a “solution”, this suggests the formulation should be free of particulate matter.

The reference to “another antimicrobial preservative” suggests that the formulation does not contain conventional antimicrobial agents (such as those discussed earlier in the patent - e.g. polyquaternium-1). [ 148 ] Dr Miller also provides his opinion on the construction of the claims.

He notes at para 71 of his affidavit that Claim 1 includes the following aspects: a multi-dose ophthalmic composition; the composition is self preserved; the concentration of zinc ions in the composition is in the range of 0.04 to 0.4 mM; and, the concentration of anions in the composition is less than 15 mM. [ 149 ] At paragraphs 72-75 he provides his opinion on the meaning of the key terms. [ 150 ] Dr Miller notes, at para 88 of his affidavit, that Claim 10 depends on any one of Claims 1-9 and requires the presence of travoprost as a therapeutically active agent and that it is the first claim in the ‘370 that specifies travoprost in the composition. [ 151 ] At para 91, Dr Miller describes Claim 13 as an independent claim directed to a topical ophthalmic solution and he sets out the aspects , i.e., the components and limits as he described at para 71. [ 152 ] At para 92, Dr Miller adds: Claim 13 includes limitations on the pH (5.5 to 5.9) and osmolality (250 to 330 mOsm/kg) of the ophthalmic solution.

The claim also specifically requires that the solution is free of BAC. The remaining elements of claim 13 all appeared previously in one or more of claims 1 to 12 and would have been understood by the skilled person in an analogous manner. [ 153 ] Dr Kent provides a proposed construction of all the claims (as do the other experts).

At para 66-68 of his affidavit, he offers the meaning of the terms used, indicating that “multi-dose” signifies that the compositions require the presence of a preservative, “self- preserved” as defined in the ‘370 refers to a composition that lacks a conventional antimicrobial preservative, and “ophthalmic composition” would be understood to include such compositions as ocular therapeutic agents. [ 154 ] At para 80 he notes that Claim 10 narrows the compositions of Claims 1-9 to those containing travoprost as a therapeutically active agent and that this is the first claim of the ‘370 to specifically require the presence of a therapeutically active agent. [ 155 ] With respect to Claim 13, Dr Kent indicates that it pertains to an ophthalmic solution that contains specific components, as set out above (and as indicated by Dr Miller).

At para 84, Dr Kent adds: Claim 13 relates to topical ophthalmic solutions that are administered topically to the eye. The solutions contain 0.004w/v% travoprost as the active ingredient. Travoprost is said in the 370 Patent to be useful to lower intraocular pressure and treat glaucoma. The solutions also contain a preservative system that includes at least boric acid, propylene glycol, sorbitol and zinc chloride at concentrations from 0.04 to 0.4 mM. These solutions are free of BAK or other antimicrobial preservatives.

According to claim 13, the solutions have limited concentrations of anionic species, that is, concentrations of less than 15 mM, and have osmolality values between 250 and 330 mOsm/kg. Finally, the solutions also contain polyoxyl 40 hydrogenated castor oil. C. Construction of Claims 10 and 13 [ 156 ] I am tasked with construing the claims at issue in an informed and purposive way through the eyes of the POSITA.

I have considered Claims 10 and 13 in the context of the Patent as a whole and with the benefit of the evidence of the experts and the submissions of the parties. [ 157 ] I have also looked at the other claims, which are not at issue, to determine the differences among the claims. [ 158 ] Claim 10 is a formula for a composition and Claim 13 is a formula for a formulation. Nothing more is promised and no proposed use is set out in the claims. In contrast, Claims 11, 12, 14 and 15 refer to the proposed use, i.e., the control of intraocular pressure.

Out of 35 claims, only four claims refer to a proposed use. [ 159 ] As Alcon notes, neither Claim 10 nor 13 refers to any reduction in side effects. The Patent suggests that the use of the compositions or formulations for the treatment of certain eye conditions, but the claims at issue do not set out any proposed use. [ 160 ] Of the 35 claims, only two, Claims 13 and 14, are ophthalmic solutions. Neither refers to the particulate matter issue nor to its resolution.

It is only the evidence of Dr Loftsson that raises this as part of the construction of the claim and its inventive concept. [ 161 ] Only two of the 35 claims refer to any enhancement; Claims 16 and 35 refer to a method of enhancing antimicrobial activity. [ 162 ] I would construe the claims as follows:

Claim 13 is an independent claim directed to topical ophthalmic solutions containing travoprost. The solutions also contain a preservative system that includes boric acid, propylene glycol, sorbitol and zinc chloride at concentrations from 0.04 to 0.4 mM. These solutions are free of BAK or other antimicrobial preservatives. The solutions have limited concentrations of anionic species, that is, concentrations of less than 15 mM, and have osmolality values between 250 and 330 mOsm/kg. The solutions also contain polyoxyl 40 hydrogenated castor oil.

Claim 10 is a dependent claim which depends on cascading dependencies among Claims 1 to 9. Claim 10 claims a multi-dose, self-preserved ophthalmic composition containing travoprost and a preservative system that includes zinc chloride, propylene glycol and sorbitol, and limited concentrations of anionic species, multivalent buffering anions, multivalent metal ions and ionized salts. XII. THE INVENTION A.

Jurisprudence and Principles regarding the Inventive Concept [ 163 ] In Apotex v Sanofi-Synthelabo , 2008 SCC 61 , [2008] 3 SCR 265 [ Plavix ] at para 77 , the Supreme Court of Canada found that the inventive concept of the claims was not readily discernable from the claims themselves. The Court noted that a bare chemical formula in a claim may not be sufficient to determine its inventiveness and if that is the case, it is acceptable to read the specification in the Patent to determine the inventive concept of the claims.

The Court cautioned that “[…] it is not permissible to read the specification in order to construe the claims more narrowly or widely than the text will allow.” [ 164 ] In Abbvie Corporation v Janssen Inc , 2014 FC 55 , [2014] FCJ No 59 [ Abbvie ] at para 123 , Justice Hughes emphasized that in applying the four part test set out in Plavix to determine obviousness, it is the inventive concept of the claims that must be identified, noting, “The Court is required to focus on the invention as claimed in the claims at issue, and not on some generalized concept of invention as expressed in the patent as a whole.” B.

Alcon’s position on the Inventive Concept [ 165 ] Alcon submits that the inventors identify two aspects of their invention as stated in the

Summary of Invention: (

i) the very low concentration of zinc ions and (ii) maintaining a concentration of buffering anions below 15 mM. [ 166 ] Alcon also submits that there are several inventive concepts for Claim 13: 1. Self-preserved solutions of travoprost may be prepared using low concentrations of zinc ions provided the concentration of anionic species is also kept low. 2.

Self-preserved solutions of travoprost may be prepared using low concentrations of zinc ions provided the concentration of anionic species is also kept low (i.e. .the solution described in (1)) combined with a borate/polyol system, where the polyol is comprised of sorbitol and propylene glycol. 3. Propylene glycol generates fewer buffering anions than other tested polyols, namely, sorbitol and mannitol. As a consequence, propylene glycol offers advantages when used in a zinc-based preservative system. 4.

The pH of a travoprost solution comprising HCO-40 and zinc must be maintained below 6.0 in order to avoid the formation of particulate matter.

These four concepts are based on the evidence of Dr Loftsson. [ 167 ] For Claim 10 (read according to Claims 9, 5, 3 and 1), Alcon submits that the inventive concepts include solutions containing travoprost using low concentrations of zinc and low concentrations of anionic species combined with a borate polyol system where the polyol is propylene glycol and sorbitol and the limits on multivalent buffering anions, metal cations, and ionized salts, all of which impact the efficacy of the zinc-based preservative system. [ 168 ] In response to Apotex’s argument that the inventive concept is not consistent with Alcon’s assertion of the promised utility, Alcon argues that the inventive concept need not be the same or consistent with the promised utility, noting that the inventive concept is how you get the invention to work whereas the utility is the use of the invention, which is simply an alternative preservative system without BAK.

C. Apotex’s position on the Inventive Concept [ 169 ] Apotex submits that Alcon’s proposed construction of the inventive concept is based on Dr Loftsson’s evidence which proposes that each element of the claim should form its own inventive concept and that this also imports information from some of the testing into its fourth inventive concept, regarding the particulate problem.

Apotex submits that such a construction is wrong in law. [ 170 ] Apotex submits the inventive concept of the asserted claims is clear; a multi-dose ophthalmic composition containing travoprost employing zinc ions together with a borate/polyol complex, in amounts sufficient to preserve the composition, thereby avoiding the need for a traditional preservative, such as BAK. The limits on anionic species are not part of the inventive concept, nor is the resolution of the potential particulate problem. D. What do the experts say?

[ 171 ] At para 231 of his affidavit, Dr Loftsson expresses the opinion that there are at least four inventive concepts, just as described above at para 166. [ 172 ] Dr Loftsson also provides his opinion on the inventive concept of Claim 10 according to Claim 9 and Claims 5, 3 and 1 in turn due to their dependant nature. [ 173 ] At para 233, Dr Loftsson states: In my view the inventive concept of this reading of claim 10 includes concepts a, b and c above. Concept d does not apply as claim 10 does not include a limitation on pH.

In addition, claim 10 includes limits on multivalent buffering anions, multivalent metal cations and ionized salts, all of which are disclosed by the inventors to impact on the efficacy of the zinc based preservative system. ( Note : The reference to a, b and c refers to the first three inventive concepts of Claim 13 as set out at para 166). [ 174 ] Dr Loftsson provides an alternative

interpretation of Claim 10 according to the composition of Claim 7, and Claims 6, 5, 3 and 1 due to their dependent nature. He indicated that the inventive concept of Claim 10 would be the same except there would be no limit on iodized salts. [ 175 ] On cross-examination, Counsel for Apotex raised several of the “further enhancements” noted at page 5 of the Patent. Dr Loftsson agrees that the reference to “the present invention can be further enhanced by the use of zinc ions in combination with borate or a borate/polyol complex” is an “add on” or “another bell and whistle” .

Dr Loftsson also agrees that the paragraph beginning at line 25 which states that the performance of the zinc-based preservative systems of the present invention is further enhanced by limiting the amount of multivalent metal cations other than zinc and limiting the amount of ionised salts are also other “bells and whistles” . [ 176 ] Counsel for Apotex continued to question Dr Loftsson in this manner at Q 399-406 and Dr Loftsson agrees that the inventors are not saying that “you need these bells and whistles to meet the needs of the invention” but rather that these are “additional bells and whistles to give you more of an enhancement” . [ 177 ] Apotex’s expert, Dr Miller refers to the inventive concept of a range of claims, and notes at para 168 of his affidavit: In my opinion, the inventive concept of claims 1 to 15 and 28 to 34 of the ‘370 Patent is multi-dose ophthalmic compositions employing zinc ions, in some cases together with a borate or a borate/polyol complex, in amounts sufficient to preserve the composition, thereby avoiding the need for BAC.

By not employing BAC in the compositions, any possibility of side effects experienced by certain patients when exposed to this preservative are avoided. [ 178 ] In his

summary of opinions, Dr Kent states at para 22 of his affidavit: In my opinion, the inventive concept of the claims of the 370 Patent relates to multi-dose ophthalmic compositions containing zinc ions in relatively low concentrations as preservatives instead of conventional preservatives such as benzalkonium chloride (“BAK”) in order to avoid the deleterious side effects on the cornea caused by BAK.

In some cases, the compositions also comprise borates and polyols. [ 179 ] At paras 95 and 140, Dr Kent sets out the inventive concept as noted above and adds: Further, as the 370 Patent explains, BAK was historically commonly used in ophthalmic compositions, but it was known to cause ocular side effects in certain subsets of patients. By replacing BAK in the compositions with zinc ions (and optionally borates and polyols), the threat of these BAK-related side effects is precluded. In my opinion, this represents an aspect of the inventive concept of the 370 Patent. E.

The Inventive Concept [ 180 ] The claims themselves provide bare chemical formulas which do not permit identification of the inventive concept without looking at the specification. [ 181 ] As noted in Abbvie , above, the focus is on the invention as claimed in the claims at issue, i.e. Claims 10 and 13, and “not on some generalized concept of invention as expressed in the patent as a whole.” [ 182 ] I note that the disclosure of the Patent repeats several times the key sentences of the

Summary of the Invention. I also note that Alcon highlighted two aspects of the invention, the low concentration of zinc ions and maintaining the concentration of buffering anions at less than 15 mM, both of which are found in the

Summary. [ 183 ] The detailed description of the invention which begins at page 6c first sets out the limits for the zinc ions, indicating a preference for zinc chloride. It then notes that “it is preferred that” the total concentration of anionic species in the compositions should be limited, “to an amount of less than 15 mM, more preferably less than 10 mM, and most preferably less than 5 mM” . It then proceeds to refer to many other preferences with respect to the components.

For example, at page 9, the Patent indicates that propylene glycol is particularly preferred in order to limit the presence of anionic species and that a borate polyol complex is preferred and a propylene glycol or combination of propylene glycol and sorbital is most preferred . [ 184 ] The Patent continues to set out other enhancements, methods and possible uses at the pages that follow. [ 185 ] The reference that Alcon relies on to support the additional inventive concept of a particular pH range to ensure against particulate matter is found at page 14. [ 186 ] While that paragraph is directive in indicating that where cationic or anionic excipients are used, the amount must be limited

and the pH range “needs to be in the range of 5.0 to 6.0, preferably in the range of 5.5 to 5.9” , the nature of this paragraph is similar to many other paragraphs in the Patent detailing the various enhancements and options that are not asserted to be inventive concepts. [ 187 ] Although Alcon argues that the inventive concepts are set out “in spades” across the Patent, I am not persuaded that some of the preferences should be regarded as inventive concepts but not others.

If a reference at page 14 is an inventive concept, then should several other references which appear to have the same level of significance similarly be inventive concepts, or should none of them be inventive concepts? [ 188 ] As noted, the key aspects set out in the

Summary of Invention are repeated several times, suggesting that the inventive concepts are highlighted in that

summary. [ 189 ] Apotex takes the position that the inventive concept is simply a multi-dose ophthalmic composition using zinc ions with, in some cases, or optionally, a borate polyol complex in amounts sufficient to preserve the composition and without BAK. [ 190 ] Alcon takes the position that each aspect of the formula set out in the claims is a separate inventive concept and also that the resolution of the particulate problem is an inventive concept. [ 191 ] The inventive concept lies somewhere between these two positions but each aspect of the formula is not a separate inventive concept. [ 192 ] Only Dr Loftsson attached significance to the reference at page 14 regarding the possible particulate problem and how it could be resolved.

However, he also indicates in his affidavit that the POSITA would know how to address the problem. The other experts also clearly indicate that a POSITA would know how to address the particulate problem. So if it is a problem, it would not be inventive to resolve the problem. Therefore, I cannot conclude that resolving the particulate problem is part of the inventive concept. [ 193 ] Dr Loftsson also agreed, when the proposition was put to him, that other preferences or enhancements were “bells and whistles”.

For example, he indicated that using zinc in combination with a borate/polyol complex was “another bell and whistle”. The other experts appear to agree that the combination of zinc and a borate polyol complex is preferred.

Dr Miller refers to “in some cases together with a borate or a borate/polyol complex” and Dr Kent says “optionally borates and polyols” . [ 194 ] Overall, the expert evidence is not particularly helpful in identifying the inventive concept. [ 195 ] The bare chemical formulas of claims 10 and 13 are specific in setting out the ingredients or elements of the composition or formulation and the applicable concentrations or limits where these are essential, for example, the concentration of zinc chloride and anionic species and the range for osmolality and pH levels. [ 196 ] The

Summary of Invention notes that certain formulation parameters must be maintained in order to utilize low levels of zinc ions. The

Summary refers to the pH and osmolality values and to the need to limit the concentration of buffering anions to less than 15 mM. I attach significance to these elements which were repeated several times in the Patent. [ 197 ] I find that the inventive concept includes these essential aspects. The Inventive Concept is a (self-preserved) multi-dose ophthalmic composition or formulation containing travoprost that does not include BAK and which uses a non-conventional preservative system that includes low levels of zinc chloride, a borate/polyol complex (or p

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